Ampreloxetine for Multiple System Atrophy

(CYPRESS Trial)

Recruiting in Palo Alto (17 mi)

+97 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Theravance Biopharma

Must not be taking: Antihypertensives, MAOIs, CYP1A2 inhibitors

Disqualifiers: Diabetes, Coronary artery disease, others

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This is a Phase 3, multi-center, randomized withdrawal study to evaluate the efficacy and durability of ampreloxetine in participants with MSA and symptomatic nOH after 20 weeks of treatment. This study includes 4 periods: Screening, open label, randomized withdrawal, and long-term treatment extension (LTE).

Will I have to stop taking my current medications?

The trial requires participants to stop taking certain medications, such as midodrine and droxidopa, at least 7 days before starting the study. Additionally, you cannot use strong CYP1A2 inhibitors or inducers within 7 days before the study, and you must not change your medication for orthostatic hypotension within 7 days before the study.

How is the drug Ampreloxetine unique for treating Multiple System Atrophy?

Ampreloxetine is unique because it targets norepinephrine reuptake, which may help manage symptoms related to autonomic dysfunction in Multiple System Atrophy, a feature not specifically addressed by other treatments. ^{1 2 3 4 5}

Eligibility Criteria

Adults over 30 with Multiple System Atrophy (MSA) and symptomatic neurogenic orthostatic hypotension (nOH), confirmed by specific criteria. Participants must not be pregnant, agree to use effective birth control, and cannot have certain cardiovascular conditions or recent substance abuse. Those on certain medications for nOH or with severe cognitive impairment are excluded.

Inclusion Criteria

I am not pregnant, breastfeeding, or planning to become pregnant during the study.

I scored at least a 4 on a specific health assessment.

Participant is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.

Exclusion Criteria

I have not had major surgery in the last 4 weeks.

I do not have any health issues or recent surgeries that would affect my participation in the study.

I have severe heart failure (NYHA Class 3 or 4).

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Open Label

Participants receive ampreloxetine as a single, oral, daily dose of active drug

12 weeks

Randomized Withdrawal

Participants are randomized to receive either ampreloxetine or placebo

8 weeks

Long-Term Extension

Participants receive ampreloxetine as a single, oral, daily dose of active drug

104 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ampreloxetine (Norepinephrine Reuptake Inhibitor)
• Placebo (Drug)

Trial Overview The trial is testing Ampreloxetine's effectiveness in treating low blood pressure due to MSA compared to a placebo. It includes an initial open label phase where everyone gets the drug, followed by a randomized withdrawal period to see if benefits last without it, and then long-term treatment.

Participant Groups

Group I: Ampreloxetine (Open Label) Active Control 1 Intervention

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 12 weeks.

Group II: Long-Term Extension Period Active Control 1 Intervention

Participants will receive ampreloxetine as a single, oral, daily dose of active drug for 104 weeks.

Group III: Ampreloxetine (Randomized Withdrawal) Placebo Group 2 Interventions

After completing the open label, participants are randomized to either ampreloxetine or placebo receiving a single, oral, daily dose of active drug or placebo for a further 8 weeks.

Ampreloxetine is already approved in United States for the following indications:

🇺🇸 Approved in United States as Ampreloxetine for:

• Symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of South Florida Ataxia Research Center Tampa, FL

University of Calgary - Health Sciences Centre Calgary, Canada

Vanderbilt University Medical Center Nashville, TN

Theravance Biopharma Investigational Site Boise, ID

More Trial Locations

Who Is Running the Clinical Trial?

Theravance Biopharma Lead Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

Comparison of tandospirone and escitalopram as a symptomatic treatment in Multiple System Atrophy-cerebellar ataxia: An open-label, non-controlled, 4 weeks observational study. [2023] Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and motor dysfunction in parkinsonism and/or cerebellar ataxia. Patients with MSA usually present with depression and anxiety symptoms. This observational study of patients with MSA-cerebellar subtype (MSA-C) with subthreshold depression/anxiety symptoms aimed to compare the efficacy of escitalopram oxalate (an antidepressant drug) and tandospirone citrate (an anxiolytic drug).

2. United States pubmed.ncbi.nlm.nih.gov

Multiple system atrophy: an update. [2013] Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that usually manifests in the early sixth decade of life and progresses relentlessly with a mean survival of 9 years. Clinically, MSA is dominated by autonomic/urogenital failure, which may be associated with either levodopa (L-dopa) -unresponsive parkinsonism in 80% of cases (MSA-P subtype) or with cerebellar ataxia in 20% of cases (MSA-C subtype). Pathologically, MSA is characterized by a neuronal multisystem degeneration and abnormal glial cytoplasmic inclusions containing alpha-synuclein aggregates. Pharmacological treatment of motor features is disappointing except for a transient L-dopa response in a minority of MSA-P patients. In contrast, autonomic and urogenital features of MSA should be identified early on, because they can be treated effectively in many instances. Neuroprotective strategies are presently unavailable, however, two multicentre European trials have been launched to evaluate the effects of riluzole and human recombinant growth hormone on disease progression in MSA. Clearly, further randomised, controlled trials are required to identify effective symptomatic or neuroprotective agents in MSA. Several in vivo models have become available to allow a careful preselection of candidate agents. Several research groups have been formed in Europe (EMSA-SG, NNIPPS) and United States (NAMSA-SG), providing a framework for coordinated trial activity in MSA.

3. United States pubmed.ncbi.nlm.nih.gov

Placebo-controlled trial of amantadine in multiple-system atrophy. [2019] Multiple-system atrophy (MSA) often presents as atypical parkinsonian syndrome with rapid progression and poor response to levodopa. Reports on the open-label use of amantadine in MSA suggest variable antiparkinsonian efficacy. The authors therefore conducted a double-blind, placebo-controlled crossover trial of amantadine in MSA patients.

4. United States pubmed.ncbi.nlm.nih.gov

Brain 5-HT1A Receptor Binding in Multiple System Atrophy: An [18 F]-MPPF PET Study. [2022] Label="BACKGROUND">Loss of medullary serotonin (5-hydroxytryptamine) neurons has been linked to respiratory disturbances in multiple system atrophy (MSA). Broader 5-hydroxytryptamine dysfunction may contribute to additional motor/nonmotor symptoms in MSA. The objective of this study was to compare brain 5-hydroxytryptamine1A receptor binding between MSA and healthy controls. Secondary objectives were to compare 5-hydroxytryptamine1A receptor binding between MSA and Parkinson's disease (PD) and to assess potential associations with motor/nonmotor symptoms in MSA.

5. Germany pubmed.ncbi.nlm.nih.gov

Novel therapeutic approaches in multiple system atrophy. [2021] Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.